The nuclear factor-?B (NF-?B) proteins are pivotal for growth, differentiation and survival of hematopoietic cells. Misregulation of NF-?B genes, caused by chromosomal translocations, aberrant gene fusions, inappropriate expression of oncogenes and gene mutations, has been found in many lymphoid diseases and contributes to the malignant transformation of B- and T-lymphocytes. Although improvements have been made in patient treatment, much remains to be understood at the molecular level to achieve more effective and longer lasting therapies. Alteration of protein degradation through the ubiquitin pathway is commonly found in the pathogenesis of lymphoid diseases. Here we propose to study the role of Fbxw7 in hematologic diseases. Fbxw7 (F-box/WD40 repeat-containing protein 7) is a member of the F-box family of proteins that functions as an ubiquitin ligase enzyme targeting specific substrates for proteasome dependent degradation. Our data have revealed that Fbxw7 regulates the NF-?B pathway in cell specific context. In multiple myeloma cells, Fbxw7 functions as a pro-survival gene by promoting the degradation of the NF-?B inhibitor, Nfkb2 (p100). In the effort of revealing the signaling pathways that regulate p100 degradation, we have identified Tao2 as the kinase that regulates the Fbxw7-p100 interaction. In Aim1, we propose to study the functional role of the Tao-Fbxw7-p100 axis and its contribution to NF-?B activation in multiple myeloma survival. Conversely, in T cell malignancies, such as T-ALL (T-cell acute lymphoblastic leukemia), Fbxw7 functions as a tumor suppressor gene, suppressing NF-?B activity. In this context, we found that Fbxw7 targets an activator of the NF-?B pathway, RelA, for proteasomal degradation. Therefore, the second objective of this application is to unravel the molecular mechanisms that allow Fbxw7 to inhibit NF-?B activity and prevent T-ALL survival (Aim2). Finally, we will broaden our studies on the ubiquitin system and its relevance in lymphoid diseases progression. In Aim3 we propose to perform functional genetic screens to identify specific ubiquitin ligases that allow survival of multiple myeloma cell. A proteasome inhibitor, bortezomib, has proven an effective treatment for multiple myeloma, rendering the ubiquitin pathway particularly appealing for providing new tools for cancer therapy. All together, the results of these studies will shed light into the molecular mechanisms that control proliferation of hematological diseases via the ubiquitin system, thus opening a new avenue for the development of therapeutics.